Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection

A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection

The primary objective of the PK Lead-in Phase of the study is to evaluate the steady state pharmacokinetics (PK) and confirm the dose of ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination (FDC) in hepatitis C virus (HCV)-infected pediatric participants. The PK Lead-in Phase will also evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of LDV/SOF FDC in HCV-infected pediatric participants.

The Treatment Phase will be initiated by age cohort after confirmation of age-appropriate LDV/SOF FDC dosage levels. Participants from the PK Lead-in Phase will immediately rollover into the Treatment Phase with no interruption of study drug administration. The primary objective of the Treatment Phase is to evaluate the antiviral efficacy, safety, and tolerability of LDV/SOF FDC +/- ribavirin (RBV) for 12 or 24 weeks in pediatric participants with HCV.

During screening, participants will receive placebo to match LDV/SOF FDC to assess ability to swallow tablets.

Study Overview

• Status: Completed
• Conditions: Hepatitis C Virus Infection
• Intervention / Treatment: Drug: LDV/SOF; Drug: RBV

• Study Type: Interventional
• Enrollment (Actual): 226
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Newcastle, New South Wales, Australia
    • Westmead, New South Wales, Australia
  • Victoria
    • Parkville, Victoria, Australia
• New Zealand
  • Auckland, New Zealand
• United Kingdom
  • England
    • Birmingham, England, United Kingdom
    • Leeds, England, United Kingdom
    • London, England, United Kingdom
  • Scotland
    • Glasgow, Scotland, United Kingdom
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • California
    • Los Angeles, California, United States
    • San Francisco, California, United States
  • Colorado
    • Aurora, Colorado, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Kentucky
    • Louisville, Kentucky, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Missouri
    • Saint Louis, Missouri, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • New York
    • New York, New York, United States
  • North Carolina
    • Chapel Hill, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Columbus, Ohio, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • Tennessee
    • Nashville, Tennessee, United States
  • Texas
    • Dallas, Texas, United States
    • Fort Worth, Texas, United States
    • San Antonio, Texas, United States
  • Washington
    • Seattle, Washington, United States
  • West Virginia
    • Morgantown, West Virginia, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Consent of parent or legal guardian required
• Chronic HCV infection
• Screening laboratory values within defined thresholds

Key Exclusion Criteria:

• History of clinically significant illness or any other medical disorder that may interfere with individual's treatment, assessment or compliance with the protocol.
• Co-infection with HIV, acute hepatitis A virus, or hepatitis B virus
• Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage)
• Pregnant or nursing females
• Known hypersensitivity to study medication
• Use of any prohibited concomitant medications as within 28 days of the Day 1 visit

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 12 to < 18 Years Old; Participants between 12 to < 18 years of age weighing ≥ 45 kg will receive LDV/SOF FDC (90/400 mg tablet or 4 x 22.5 mg/100 mg tablets or 8 x 11.25/50 mg granules based on swallowability assessment during screening). Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment. United Kingdom: HCV genotypes (GT) 1, 4, 5, or 6 treatment-naive (TN) with or without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 treatment-experienced (TE) without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks; HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks United States/Australia/New Zealand: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks; HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks; HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks	Drug: LDV/SOF; LDV/SOF FDC administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight; Other Names: REBETOL®
Experimental: 6 to < 12 Years Old; Participants between 6 to < 12 years of age weighing ≥ 17 kg and < 45 kg will receive LDV/SOF FDC (45/200 mg as 2 x 22.5/100 mg tablets or 4 x 11.25/50 mg granules based on swallowability assessment during screening). Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment. United Kingdom: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks; HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks United States/Australia/New Zealand: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks; HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks; HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks	Drug: LDV/SOF; LDV/SOF FDC administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight; Other Names: REBETOL®
Experimental: 3 to < 6 Years Old; Participants between 3 to < 6 years of age weighing ≥ 17 kg will receive LDV/SOF FDC (45/200 mg granules as 4 x 11.25/50 mg packets) and participants weighing < 17 kg will receive LDV/SOF FDC (33.75/150 mg oral granules as 3 x 11.25/50 mg packets). Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment. United Kingdom: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks; HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks United States/Australia/New Zealand: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks; HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks; HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks; HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks	Drug: LDV/SOF; LDV/SOF FDC administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight; Other Names: REBETOL®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For Participants in the PK Lead-in Phase, Pharmacokinetic (PK) Parameter: AUCtau of GS-331007 (Metabolite of SOF), LDV, and SOF	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Cohorts 1 and 2 (6 to < 18 years of age): predose, 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose on Day 10; Cohort 3 (3 to < 6 years of age): predose, 0.5, 2, 4, 8, and 12 hours postdose on Day 10
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event During the PK Lead-in Phase or the Treatment Phase		Up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For Participants in the PK Lead-in Phase, Change From Baseline in HCV RNA		Baseline; Weeks 1, 2, 4, 8, and 12
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event During the PK Lead-in Phase		Up to Day 10
For the Treatment Phase, Percentage of Participants With Sustained Virologic Response (SVR) at 4 Weeks After Discontinuation of Therapy (SVR4)	SVR4 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 4 weeks after stopping study treatment.	Posttreatment Week 4
For the Treatment Phase, Percentage of Participants With SVR at 12 Weeks After Discontinuation of Therapy (SVR12)	SVR12 was defined as HCV RNA < LLOQ at 12 weeks after stopping study treatment.	Posttreatment Week 12
For the Treatment Phase, Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24)	SVR24 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment.	Posttreatment Week 24
For the Treatment Phase, Percentage of Participants Experiencing Viral Breakthrough	Viral breakthrough was defined as having confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment.	Up to 24 weeks
For the Treatment Phase, Percentage of Participants Experiencing Viral Relapse	Viral relapse was defined as having confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.	Up to Posttreatment Week 24
For the Treatment Phase, Change From Baseline in HCV RNA		Baseline; Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only)
For the Treatment Phase, Percentage of Participants With HCV RNA < LLOQ While On Treatment		Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only)
For the Treatment Phase, Percentage of Participants With Alanine Aminotransferase (ALT) Normalization	ALT normalization was defined as ALT > the upper limit of normal (ULN) at baseline and ALT ≤ ULN at each visit.	Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only), and Posttreatment Week 4
For the Treatment Phase, Change From Baseline in Height		Baseline; Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only), and Posttreatment Weeks 4, 12, and 24
For the Treatment Phase, Change From Baseline in Weight		Baseline; Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only), and Posttreatment Weeks 4, 12, and 24
For the Treatment Phase, Number of Male Participants With a Change From Baseline in Tanner Stage for Pubic Hair	Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented.	Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24
For the Treatment Phase, Number of Male Participants With a Change From Baseline in Tanner Stage for Genitalia Development	Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented.	Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24
For the Treatment Phase, Number of Female Participants With a Change From Baseline in Tanner Stage for Pubic Hair	Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented.	Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24
For the Treatment Phase, Number of Female Participants With a Change From Baseline in Tanner Stage for Breast Development	Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented.	Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24
Acceptability of LDV/SOF Tablets as Measured by the Percentage of Participants Able/Unable to Swallow Placebo Tablet at Day 1	Participants who were able/unable to swallow placebo tablets were assessed. Participants 12 to < 18 years old were first asked to perform the swallowability assessment using the 90/400 mg placebo tablet. If they were unable to swallow this, they were then asked to perform the swallowability assessment with 22.5/100 mg placebo tablets. Participants 6 to < 12 years old were to be assessed with the 22.5/100 mg placebo tablets. However, 8 participants were mistakenly assessed using the 90/400 mg placebo tablet.	Day 1
Acceptability of LDV/SOF Granules as Measured by Palatability at Day 1	Participants who were dosed with granules were asked if they tasted the study drug. If they tasted it, then they were asked to provide a number from 0 to 100 to rate the taste of the study drug, with higher scores indicating better taste. Data was then summarized as percentage of participants choosing the following palatability categories: 1) Did not taste the study drug, 2) Tasted drug with score > 60 to 100, 3) Tasted drug with score 40 to 60, and 4) Tasted drug with score of 0 to < 40.	Day 1

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Kirby B, German P, Kanwar B, Ni L, Lakatos I, Ling J, Mathias A. Pharmacokinetics of Once-Daily Sofosbuvir and Ledipasvir/Sofosbuvir in HCV-Infected Adolescents. Hepatology 2015;62 (S1): 1040A-1041A
• Garrison KL, Mathias A, Kersey K, Kanwar B, Ni L, Jain A, et al. Pharmacokinetics of Once-Daily Sofosbuvir and Ledipasvir/Sofosbuvir in HCV-Infected Pediatrics Aged 6 to < 12 Years Old. Hepatology 2016;64 (S1): 436A
• Schwarz K, Murray KF, Rosenthal P, Bansal S, Lin CH, Ni L, et al. High Rates of SVR12 in Adolescents Treated with the Combination of Ledipasvir/Sofosbuvir. J Hepatol 2016; 64 (2): S184-S185
• K.F. Murray, W. Balistreri, S. Bansal, S. Whitworth, H. Evans, R.P. Gonzalez-Peralta, et al. Ledipasvir/sofosbuvir ± ribavirin for 12 or 24 weeks is safe and effective in children 6-11 years old with chronic hepatitis C infection. J Hepatol 2017;66: S33-S62
• Balistreri WF, Murray KF, Rosenthal P, Bansal S, Lin CH, Kersey K, Massetto B, Zhu Y, Kanwar B, German P, Svarovskaia E, Brainard DM, Wen J, Gonzalez-Peralta RP, Jonas MM, Schwarz K. The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection. Hepatology. 2017 Aug;66(2):371-378. doi: 10.1002/hep.28995. Epub 2017 Jun 19.
• Younossi ZM, Stepanova M, Balistreri W, Schwarz K, Murray KF, Rosenthal P, Bansal S, Hunt S. Health-related Quality of Life in Adolescent Patients With Hepatitis C Genotype 1 Treated With Sofosbuvir and Ledipasvir. J Pediatr Gastroenterol Nutr. 2018 Jan;66(1):112-116. doi: 10.1097/MPG.0000000000001754.
• Begley R, Meng A, Massetto B, Shao J, Ling J, and Mathias A. Pharmacokinetics of Once Daily Sofosbuvir or Ledipasvir/Sofosbuvir in HCV-Infected Pediatrics Aged 3 to <6 Years Old. Hepatology 2018;68 (S1): 582A.
• Schwarz KB, Rosenthal P, Murray KF, Honegger JR, Hardikar W, Hague R, Mittal N, Massetto B, Brainard DM, Hsueh CH, Shao J, Parhy B, Narkewicz MR, Rao GS, Whitworth S, Bansal S, Balistreri WF. Ledipasvir-Sofosbuvir for 12 Weeks in Children 3 to <6 Years Old With Chronic Hepatitis C. Hepatology. 2020 Feb;71(2):422-430. doi: 10.1002/hep.30830. Epub 2019 Aug 19.
• Murray KF, Balistreri WF, Bansal S, Whitworth S, Evans HM, Gonzalez-Peralta RP, Wen J, Massetto B, Kersey K, Shao J, Garrison KL, Parhy B, Brainard DM, Arnon R, Gillis LA, Jonas MM, Lin CH, Narkewicz MR, Schwarz K, Rosenthal P. Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6-11. Hepatology. 2018 Dec;68(6):2158-2166. doi: 10.1002/hep.30123. Epub 2018 Nov 17.

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2014
• Primary Completion (Actual): June 15, 2018
• Study Completion (Actual): August 24, 2018

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: September 23, 2014
• First Posted (Estimate): September 25, 2014

Study Record Updates

• Last Update Posted (Actual): March 2, 2020
• Last Update Submitted That Met QC Criteria: February 18, 2020
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Infections; Communicable Diseases; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Sofosbuvir; Ribavirin; Ledipasvir, sofosbuvir drug combination; Ledipasvir
• Other Study ID Numbers: GS-US-337-1116; 2014-003578-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No